Table 4.
Influence of cannabinoids on ACE2 activity and other relevant effects in the fight against COVID-19.
| Model | Agonists | Effects | Final Conclusion of Authors | References |
|---|---|---|---|---|
| human iPSC- cardiomyocytes infected with SARS-CoV-2 | WIN55212-2 | ↔ ACE2 levels; ↔viral infection and replication; ↓release of proinflammatory cytokines and cytotoxic damage |
therapeutic potential of cannabinoids in protecting the heart against SARS-CoV-2 infection is not related to modification of ACE2 levels | [99] |
| in silico docking studies | CBD THC CBN |
CBD: hACE2 (↓), main virus protease activity ↓ THC: hACE2 and main virus protease (↓) CBN: inactive |
THC and CBD might inhibit the SARS-CoV-2 infection via their influence on hACE2 and viral proteases | [101] |
| in silico docking studies | 8 phyto-compounds derived from cannabis, including CBD, THC, and CVN | CBD and CVN showed the strongest potency in docking to ACE2, TMPRSS2, NRP1, IL-6, and TNF-α | CBD and CVN may be beneficial for the treatment of COVID-19 and post-COVID-19 neuronal symptoms | [102] |
| artificial 3D human models of oral, airway, and intestinal tissues treated with TNF-α and IFN-γ | 13 high-CBD Cannabis sativa extracts | ↓ACE2 and TMPRSS2 in oral, lung, and intestinal epithelia constituting important routes of SARS-CoV-2 invasion | Cannabis sativa extracts may become a useful and safe addition to the prevention/treatment of COVID-19 as an adjunct therapy; the modulation of ACE2 levels may be an effective strategy for decreasing disease susceptibility | [103] |
| alveolar epithelial A549 cell line macrophage cell line KG1 |
extract from Cannabis sativa strain Arbel (CBD, CBG, THVC, and terpenes) |
A549: ↓ACE2 expression together with ↓IL-6, IL-8, CCL2 macrophage: ↑IL-6 and ↑IL-8 levels |
further studies are needed to determine the therapeutic significance of cannabis in COVID-19 treatment due to its positive (A549 cells) and negative effects (macrophages) | [104] |
| human colon Caco-2 cell line | CBD | ↓ACE2 (concentration-dependent) ↑cell viability, ↓all proinflammatory markers | further studies are needed to clarify the consequences of ACE2 down-regulation and its impact on susceptibility to SARS-CoV-2 | [105] |
| human lung fibroblast WI-38 | high-CBD/low-THC cannabis extracts CBD |
↓ACE2, TMPRSS, COX2, IL-6, and IL-8 ↓ACE2, TMPRSS |
further studies are needed to identify the proper ratios of a combination of single ingredients to find an ideal formulation for future potential clinical studies/use | [31] |
| human H1299 lung adenocarcinoma cells | industrial hemp essential oil: E-caryophyllene and α-pinene were the prominent terpenes and CBDA was the main terpenophenol | ↓gene expression of ACE2 and TMPRSS2 | hemp essential oils are promising agents to be further investigated with the final goal of optimizing their use in protective devices for counteracting the SARS-CoV-2 virus entry into the human host | [106] |
| Caco-2 293T-ACE2 Vero E6 cell lines |
extracts of hemp and isolates of specific cannabinoids: CBDA and CBGA | cannabinoid acids (CBDA and CBGA) lower SARS-CoV-2 entry into Vero E6 cells through spike binding | CBDA and CBGA (allosterically) block cellular entry of pseudovirus and live SARS-CoV-2 alpha variant B.1.1.7 and beta variant B.1.351 | [107] |
↓—decrease; (↓)—moderate decrease; ↑—increase; ↔—no change; ACE2, angiotensin-converting enzyme 2; Caco-2, human colorectal adenocarcinoma cell line; CBD, cannabidiol; CBDA, cannabidiolic acid; CBG, cannabigerol; CBGA; cannabigerolic acid; CBN, cannabinol; CCL2, C–C Motif Chemokine Ligands (CCLs) 2; COX2, cyclooxygenase 2; COVID-19; coronavirus disease 2019; CVN, cannabivarin; hACE2, human angiotensin-converting enzyme; hiPSC-CMs, human iPSC-derived cardiomyocytes; IL-6, interleukin-6; IL-8, interleukin-8; NRP1, neuropilin-1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2; THC, Δ⁹-tetrahydrocannabinol; TNF-α, tumor necrosis factor α.